The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease

Zhihua Liu, Jinwoo Lee, Scott Krummey, Wei Lu, Huaibin Cai, Michael J. Lenardo

Research output: Contribution to journalArticlepeer-review

Abstract

Leucine-rich repeat kinase 2 (LRRK2) has been identified by genome-wide association studies as being encoded by a major susceptibility gene for Crohn's disease. Here we found that LRRK2 deficiency conferred enhanced susceptibility to experimental colitis in mice. Mechanistic studies showed that LRRK2 was a potent negative regulator of the transcription factor NFAT and was a component of a complex that included the large noncoding RNA NRON (an NFAT repressor). Furthermore, the risk-associated allele encoding LRRK2 Met2397 identified by a genome-wide association study for Crohn's disease resulted in less LRRK2 protein post-translationally. Severe colitis in LRRK2-deficient mice was associated with enhanced nuclear localization of NFAT1. Thus, our study defines a new step in the control of NFAT activation that involves an immunoregulatory function of LRRK2 and has important implications for inflammatory bowel disease.

Original languageEnglish (US)
Pages (from-to)1063-1070
Number of pages8
JournalNature Immunology
Volume12
Issue number11
DOIs
StatePublished - Nov 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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